Anatomic and chromosomal anomalies in 639 spontaneous abortuses

Summary A total of 639 spontaneous abortuses collected in a maternity hospital were set up in culture. This sample included 565 unselected consecutive abortuses and 74 selected abortuses ascertained by morphology and/or clinical history. Among these, 339 were incomplete specimens with no recovered embryo or fetus, 110 were anatomically apparently normal and 190 were grossly abnormal. In the unselected series, 565 specimens were cultured and 402 were karyotyped; 215 (53.5%) were chromosomally abnormal. In the selected series, 74 specimens were set up in culture and 45 were karyotyped; 26 (57.7%) had an abnormal karyotype. In all, successful karyotyping was done on 447 abortuses (70%), of which 339 were studied with banding. One or more major chromosome abnormalities were detected in 241 (54%) of the karyotyped cases, 230 of which were numerical anomalies and 11 structural anomalies. Numerical anomalies included primary autosomal trisomies (31% of the total karyotyped), 45,X (10%), triploidy (6.5%), and tetraploidy (1.8%). Of the 22 types of autosomal trisomies possible, all except those for 1, 5, 17, and 19 were identified. An abortus with a 49,XX,+2,+5,+8 karyotype was detected. The excess autosomal material present in the triple trisomic abortus corresponded to 10% of the haploid autosomal complement. Of the 11 abortuses with structural abnormalities, seven were inherited while the other four were sporadic. The survival rate of 45,X conceptuses was estimated to be one in 300.     

Genetic analysis of juvenile periodontitis in families ascertained through an affected proband.

Data from 28 families ascertained through a proband with juvenile periodontitis were used to test a series of Mendelian models of inheritance that included both autosomal and X-linked transmission. There was strong evidence of familial aggregation of this progressive dental disease, and the best-fitting model was an autosomal recessive model. Because of the rather limited age range for expression of the disease in this situation, simulations were done, in a model-choice analysis using samples of this size, to assess the chance of mistaking an autosomal dominant disease (with masking of the affected phenotype outside a specified age range) for an autosomal recessive disease. While the rate of Type II error was fairly high (40%) when competing models in these simulations were compared, these data suggest that it is reasonable to infer that juvenile periodontitis is an autosomal recessive disorder.     

Clinical and genetic heterogeneity in retinitis pigmentosa

Summary The clinical course of defective vision and blindness has been investigated in relation to different modes of genetic transmission in a large series of 93 families with retinitis pigmentosa (RP). For autosomal dominant RP, two clinical subtypes could be distinguished according to the delay in macular involvement. In the severe form, macular involvement occurred within 10 years, while in the mild form, macular involvement occurred after 20 years. Interestingly, a significant increase of mean paternal age (38.8 years, mean controls in France = 29.1 years, P < 0.001) was found in this form of RP, a feature which is suggestive of new mutations. For autosomal recessive RP, four significantly different clinical subtypes could be recognized, according to both age of onset and the pattern of development (P < 0.001), namely cone-rod dystrophy and early-onset severe forms on the one hand (mean age of onset = 7.6 years), late-onset mild forms and senile forms on the other. Similarly, two significantly different clinical subtypes could be recognized in X-linked RP, according to both mode and age of onset, which were either myopia (mean age = 3.5±0.5 years) or night blindness (mean age = 10.6±4.1 years, P < 0.001). By contrast, no difference was noted regarding the clinical course of the disease, which was remarkably severe whatever the clinical subtype (blindness before 25 years). In addition, all obligate carriers in our series were found to have either severe myopia or pigment deposits in their peripheral retina. Finally, sporadic RP represented the majority of cases in our series (42%). There was a considerable heterogeneity in this group, and at least three clinical forms could be recognized, namely cone-rod dystrophy, early onset-severe forms and late onset moderate forms. At the beginning of the disease, the hereditary nature of the sporadic forms was very difficult to ascertain (especially between 7–10 years) and only the clinical course could possibly provide information regarding the mode of inheritance. However, the high level of consanguinity, and the high sex ratio in early onset and severe sporadic forms (including cone-rod dystrophy), was suggestive of an autosomal or X-linked recessive inheritance, while increased paternal age in late onset forms was suggestive of autosomal dominant mutations.     

Cytogenetic studies in spontaneous abortion: the Calgary experience

In a series of 493 apparently consecutive products of spontaneous abortions obtained for cytogenetic studies, tissue culture was attempted in 428 cases; chromosome analysis using the Q-banding technique was completed in 215 cases (50.2%). Abnormal karyotypes were identified in 80 cases (37.2%). Maternal tissue contamination was apparent and the actual frequency of karyotypic abnormal abortuses could be as high as 50%. Comparison of the frequency of a specific type of chromosome abnormalities with nine other series of studies showed the lowest frequency of autosomal trisomies and the highest frequency of triploidies and structural aberrations in the Calgary series. In addition, a significantly lower gestational age was observed for triploidies 69, XXX as compared to the 69, XXY.     

Evidence for autosomal dominant inheritance of prostate cancer.

A family-history cancer survey was conducted on 5,486 men who underwent a radical prostatectomy, for clinically localized prostate cancer, in the Department of Urology at the Mayo Clinic during 1966-95; 4,288 men responded to the survey. Complex segregation analysis was performed to assess the genetic basis of age at diagnosis and the familial clustering of prostate cancer. For the total group, no single-gene model of inheritance clearly explained familial clustering of disease, which could be partly explained by lack of Hardy-Weinberg equilibrium, with an excess of homozygotes. After accounting for deviations from Hardy-Weinberg equilibrium, the best-fitting model that explained the familial aggregation and age at diagnosis was a rare autosomal dominant susceptibility gene, and this model fitted best when probands were diagnosed at <60 years of age. The model predicts that the frequency of the susceptibility gene in the population is .006 and that the risk of prostate cancer by age 85 years is 89% among carriers of the gene and 3% among noncarriers. A strength of our study is its large size, such that genetic models could be fitted within strata defined by the age of the proband. Although the autosomal dominant model was consistently the best model, the parameter estimates differed somewhat (P=.03) across the different age groups, suggesting genetic heterogeneity. Additional evidence that the hereditary basis of prostate cancer is likely to be genetically complex was provided by the following: (1) there was a significantly elevated age-adjusted risk of prostate cancer among brothers of probands, compared with their fathers (relative risk 1.5 [95% confidence interval 1.4-1.7]); (2) the autosomal dominant model predicted an excess of homozygotes, over that predicted by Hardy-Weinberg equilibrium; and (3) the model-predicted risk of prostate cancer among relatives was inadequate when probands were diagnosed at age >=70 years.     

Dentition and tooth replacement pattern in Chalcides (Squamata; Scincidae)

This study was undertaken as a prerequisite to investigations on tooth differentiation in a squamate, the Canarian scincid Chalcides. Our main goal was to determine whether the pattern of tooth replacement, known to be regular in lizards, could be helpful to predict accurately any stage of tooth development. A growth series of 20 laboratory-reared specimens, aged from 0.5 month after birth to about 6 years, was used. The dentition (functional and replacement teeth) was studied from radiographs of jaw quadrants. The number of tooth positions, the tooth number in relation to age and to seasons, and the size of the replacement teeth were recorded. In Chalcides, a single row of pleurodont functional teeth lies at the labial margin of the dentary, premaxillary, and maxillary. Whatever the age of the specimens, 16 tooth positions were recorded, on average, in each quadrant, suggesting that positions are maintained throughout life. Replacement teeth were numerous whatever the age and season, while the number of functional teeth was subject to variation. Symmetry of tooth development was evaluated by comparing teeth two by two from the opposite side in the four jaw quadrants of several specimens. Although the relative size of some replacement teeth fitted perfectly, the symmetry criterion was not reliable to predict the developmental stage of the opposite tooth, whether the pair of teeth compared was left-right or upper-lower. The best fit was found when comparing the size of successive replacement teeth from the front to the back of the jaw. Every replacement tooth that is 40-80% of its definitive size is followed, in the next position on the arcade, by a tooth that is, on average, 20% less developed. Considering teeth in alternate positions (even and odd series), each replacement tooth was a little more developed than the previous, more anterior, one (0.5-20% when the teeth are from 10-40% of their final size). The latter pattern showed that tooth replacement occurred in alternate positions from back to front, forming more or less regular rows (i.e., "Zahnreihen"). In Chalcides, the developmental stage of a replacement tooth in a position p can be accurately predicted provided the developmental stage of the replacement tooth in position p-1 or, to a lesser degree, in position p-2 is known. This finding will be particularly helpful when starting our structural and ultrastructural studies of tooth differentiation in this lizard.     

Population genetic studies of retinitis pigmentosa.

A questionnaire survey characterized a sample of 670 probands with retinitis pigmentosa (RP) and allied disorders. Segregation analysis provided some evidence for a small proportion of sporadic cases and for decreased segregation ratios of the dominant and recessive genotypes, which could be attributed to delayed age of onset in some cases. The overall incidence of RP was indirectly calculated to be approximately 1 in 3,700, while the incidence of autosomal recessive RP, including at least two genocopies, was estimated to be about 1 in 4,450. Family data analysis included the calculation of the likelihood that each family represented autosomal recessive, autosomal dominant, and X-linked inheritance patterns. These likelihoods were then converted to relative probabilities and summed over the sample population to yield estimates of the proportions of the three Mendelian types. This large, heterogeneous sample indicated that approximately 84% of the cases in the United States may be autosomal recessive, while about 10% are dominant and 6% X-linked recessive.     

The diagnostic reliability of cytologic typing in primary lung cancer with a review of the literature

To evaluate the growing tendency in recent years to attribute more diagnostic reliability to cytologic methods, we investigated the accuracy of cytologic typing in specimens obtained from bronchopulmonary material by five different clinical sampling methods, comparing the cytologic diagnoses with the known histologic diagnoses. The study consisted of 232 cytologic specimens from 157 cases of primary lung cancer. Of the 232 specimens, 173 (75%) were correctly typed and 59 (25%) incorrectly typed with respect to the appropriate histologic diagnoses. When all sampling methods were considered together, the study demonstrated that well-differentiated epidermoid carcinoma and "oat cell" and spindle-polygonal anaplastic carcinomas yielded high cytologic typing accuracies. In poorly differentiated tumors, bronchioloalveolar cell carcinoma and bronchogenic adenocarcinoma, the correct cytologic typing was much lower. The different tumor types and their degrees of differentiation seem to be the decisive factors in cytologic typing accuracy. The findings of this study were compared with those of others and were found to be consistent with the results of even larger series of cases. For some types the typing accuracy was higher than that reported in other series, whereas for other types, e.g., adenocarcinomas, it was lower.     

Calcium oxalate crystals in thyroid fine needle aspiration cytology

OBJECTIVE: To determine the occurrence, distribution and location of calcium oxalate crystals (COCs) in thyroid fine needle cytology specimens. STUDY DESIGN: Thyroid tissues from 60 fine needle aspiration cytology specimens (31 benign and 29 malignant lesions) were reviewed. These lesions were also histologically examined, and their pathologic diagnosis was confirmed. The cytologic slides were examined by normal and polarized light microscopy to determine their size, shape, occurrence, distribution and location. RESULTS: The size and shape of COCs varied from case to case. The total incidence was 45% (benign diseases, 68%; malignant lesions, 21%). No significant relationship between age and occurrence of COCs was found. Benign diseases showed more multifocal than focal distribution of COCs, unlike malignant diseases. Twenty-three (85%) of 27 cases with COCs revealed background location of COCs, especially within thyroid colloid. CONCLUSION: The occurrence of COCs in thyroid fine needle cytology was lower than that in histologic specimens reported in the literature, and COCs were more often identified in benign than malignant lesions. The presence of COCs may be a clue to benign lesions if their distribution is taken into consideration.     

Clinical, laboratory, and genetic investigations of hypophosphatasia: support for autosomal dominant inheritance with homozygous lethality

This article presents detailed clinical and laboratory investigations of six hypophosphatasia kindreds. Serum alkaline phosphatase and urinary phosphoethanolamine comparisons between the affected population and a normal control population demonstrate these parameters routinely identify the heterozygous individual when age and sex variations are accounted for. Using clinical data from the kindred population and a detailed review of the literature, the type and frequency of clinical findings for both the homozygous and heterozygous genotype are enumerated. The clinical and biochemical phenotypes were subjected to segregation analysis. When the results of these analyses are viewed in light of their mathematical limitations and the genetic precepts of autosomal dominant and recessive inheritance, hypophosphatasia is best described as an autosomal dominant disorder with 85% penetrance and homozygous lethality.     

Chromosomal mosaicism in spontaneous abortions: Analysis of 650 cases

It is known that up to 50% spontaneous abortions (SA) in the first trimester of pregnancy are associated with chromosomal abnormalities. We studied mosaic forms of chromosomal abnormalities in 650 SA specimens using interphase MFISH and DNA probes for chromosomes 1, 9, 13/21, 14/22, 15, 16, 18, X, and Y. Numerical chromosomal abnormalities were discovered in 58.2% (378 cases). They contained combined chromosomal abnormalities (aneuploidy of several chromosomes or aneuploidy in combination with polyploidy in the same specimen) in 7.7% (29 cases) or 4.5% of the entire SA sample; autosomal trisomy, in 45% (18.2% in chromosome 16, 8.9% in chromosomes 14/22, 7.9% in chromosomes 13/21, 3.1% in chromosome 18, and 1.4% in chromosome 9). Chromosome X aneuploidy was found in 27% cases, among which 9.6% represented chromosome X monosomy. Polyploidy was observed in 22.9% cases. In 5.1% cases, we observed mosaic form of autosomal monosomy. Among the SA cases with chromosomal abnormalities mosaicism was observed in 50.3% (∼ 25% of the entire SA sample). The results of the present study indicate that significant amount of chromosomal abnormalities in SA cells are associated with disturbances in mitotic chromosome separation, which represents the most common cause of intrauterine fetal death. It was also shown that original collection of DNA probes and the technique of interphase MFISH could be useful for detection of chromosomal mosaicism in prenatal cell specimens.     

Role of the calcaneal heel pad and polymeric shock absorbers in attenuation of heel strike impact

The capacity of the calcaneal heel pad, with and without augmentation by a polymeric shock absorbing material (Sorbothane^® 0050), to attenuate heel strike impulses has been studied using five fresh human cadaveric lower leg specimens. The specimens, instrumented with an accelerometer, were suspended and impacted with a hammer; a steel rod was similarly suspended and impacted. The calcaneal heel pad attenuated the peak accelerations by 80%. Attenuations of up to 93% were achieved by the shock absorbing material when tested against the steel rod; however, when tested in series with the calcaneal heel pad, the reduction in peak acceleration due to the shock absorbing material dropped to 18%. Any evaluation of the effectiveness of shock absorbing shoe materials must take into account their mechanical interaction with the body.     

ATM-heterozygous germline mutations contribute to breast cancer-susceptibility

Approximately 0.5%-1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived >/=5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T-->G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are "A-T disease-causing" mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.     

Linkage of familial dilated cardiomyopathy to chromosome 9. Heart Muscle Disease Study Group.

Idiopathic dilated cardiomyopathy is a heart muscle disease of unknown etiology, characterized by impaired myocardial contractility and ventricular dilatation. The disorder is an important cause of morbidity and mortality and represents the chief indication for heart transplantation. Familial transmission is often recognized (familial dilated cardiomyopathy, or FDC), mostly with autosomal dominant inheritance. In order to understand the molecular genetic basis of the disease, a large six-generation kindred with autosomal dominant FDC was studied for linkage analysis. A genome-wide search was undertaken after a large series of candidate genes were excluded and was then extended to two other families with autosomal dominant pattern of transmission and identical clinical features. Coinheritance of the disease gene was excluded for > 95% of the genome, after 251 polymorphic markers were analyzed. Linkage was found for chromosome 9q13-q22, with a maximum multipoint lod score of 4.2. There was no evidence of heterogeneity. The FDC locus was placed in the interval between loci D9S153 and D9S152. Several candidate genes for causing dilated cardiomyopathy map in this region.     

Attitudes of young patients with Parkinson's disease towards possible presymptomatic and prenatal genetic testing

OBJECTIVE: To evaluate the opinions and attitudes of young patients with Parkinson's disease (PD) towards possible presymptomatic and prenatal genetic testing for their illness. Background: With progress in understanding of the genetic component in the etiology of PD, presymptomatic genetic testing may become available in subgroups of patients. METHODS: During a survey on sociodemographic and risk factors 111 PD patients (mean age 45 years: mean age at PD onset 36 years) were given a questionnaire with six items about possible presymptomatic and prenatal genetic testing. RESULTS: Fifty-seven patients (5196) had knowledge about presymptomatic and prenatal testing. Eighty patients (72%) would take a presymptomatic test, if they had an autosomal dominant form of PD and if the test were available. The most Important reasons given for taking the test were planning of partnership (40%) and family (48%). When being identified as a carrier of a presumed "Parkinson gene", 78 patients (70%) would decide not to have children. Sixty-three patients (57%) would choose to have prenatal testing. Attitudes were largely independent of sociodemographic and disease variables. CONCLUSIONS: When addressed as hypothetical persons at genetic risk, young patients with PD support possible presymptomatic genetic testing and, to a lesser extent, prenatal testing. Attitudes and reasons to participate in such hypothetical testing do not grossly differ from those of at-risk persons in established single-gene autosomal dominant disorders of late onset.     

Differences in the error mechanisms affecting sex and autosomal chromosomes in women of different ages within the reproductive age group.

Aneuploidy was assessed in lymphocyte cultures from 16 women aged between 20 and 50. Between 236 and 1,677 cells were studied per subject and the gains and losses of each chromosome recorded. The X chromosome was found to show the same ratio of loss to gain (approximately 3:1) at all ages, but the frequency of total aneuploidy (loss plus gain) showed a significant increase with age. By contrast, there was no clear association of the frequency of autosomal chromosome aneuploidy with age, but the ratio of loss to gain was significantly greater in younger women (aged 21-35) than in older women (aged 36-50). Thus, X chromosomes in females are affected by a mechanism of error different to that affecting autosomal chromosomes. Although the ratio of loss to gain changes, the relative involvement of the different autosomal chromosomes is unchanged with age. Thus, the initial "recruitment" of chromosomes undergoing error is the same in both groups, but the "processing" of these chromosomes is different. Since the relative involvement of autosomes in aneuploidy mimics their relative involvement in displacement, it is proposed that displacement is the initial or "recruitment" step in error. "Processing" then commonly involves "chromosome elimination" in younger women and more frequent "random segregation" in older women.     

Cytologic findings in vitreous fluids. Analysis of 74 specimens

OBJECTIVE: To review the cytologic findings of vitreous specimens and propose a simplified approach to them. STUDY DESIGN: Seventy-four vitreous specimens from 60 patients obtained either during a pars plana vitrectomy or by vitreous aspiration were reviewed. Clinical correlation was obtained on all patients. RESULTS: Findings suggestive of a specific disorder were present in 30 specimens (41%); cytologic examination of the remaining 44 showed nonspecific changes. A lymphoproliferative disorder, the intraocular malignancy suspected most often in this series, was identified in eight specimens (11%). Large cell lymphomas were evident in 5 specimens, 2 specimens were suspicious for lymphoma, and 1 specimen was consistent with plasmacytoma. Twelve specimens (16%) contained hemorrhage. In rare instances, specific infectious agents, such as parasites (5%), bacteria (1%) and fungi (3%), could be identified. The diagnosis of viral infections required ancillary studies. Lens fragments were identified in four cases (5%), and a diagnosis of lens-induced endophthalmitis could be rendered in one case (1%). Changes consistent with sarcoidosis were present in 3% of cases. CONCLUSION: Based on this experience with vitreous specimens submitted for clinical reasons, we found that they could be divided into three broad diagnostic categories: inflammation/infection (54 specimens/41 patients), hemorrhage (12 specimens/12 patients) and malignancy (8 specimens/7 patients).     

Carcinoma in situ specimen classification based on intermediate cell measurements

In this study the possibility of classifying carcinoma in situ and normal specimens by measuring normal-appearing intermediate cells was explored. Twenty-five histologically verified carcinoma in situ specimens and 99 normal specimens, matched with the abnormal specimens for age and use or nonuse of an oral hormonal contraceptive, were examined. The smears were monolayer preparations stained with Thionin-Feulgen Congo red. Twenty-one nuclear features were measured. A discrimination among the experimental groups could be made on the basis of the relationship between two features, area and average optical density (AOD). A regression of AOD on area for each smear was performed. The correlation, coefficient of variation, slope, intercept, as well as the mean of the AOD level and the age of the subject were used in a discriminant analysis. This resulted in a smear classification with a false-positive rate of 14% and a missed-positive rate of 32%. When contraceptive use was taken into account the overall classification was improved with a false-positive rate of 12% and a missed-positive rate of 20%.     

Evidence for high frequency of chromosomal mosaicism in spontaneous abortions revealed by interphase FISH analysis.

Numerical chromosomal imbalances are a common feature of spontaneous abortions. However, the incidence of mosaic forms of chromosomal abnormalities has not been evaluated. We have applied interphase multicolor fluorescence in situ hybridization using original DNA probes for chromosomes 1, 9, 13, 14, 15, 16, 18, 21, 22, X, and Y to study chromosomal abnormalities in 148 specimens of spontaneous abortions. We have detected chromosomal abnormalities in 89/148 (60.1%) of specimens. Among them, aneuploidy was detected in 74 samples (83.1%). In the remaining samples, polyploidy was detected. The mosaic forms of chromosome abnormality, including autosomal and sex chromosomal aneuploidies and polyploidy (31 and 12 cases, respectively), were observed in 43/89 (48.3%) of specimens. The most frequent mosaic form of aneuploidy was related to chromosome X (19 cases). The frequency of mosaic forms of chromosomal abnormalities in samples with male chromosomal complement was 50% (16/32 chromosomally abnormal), and in samples with female chromosomal complement, it was 47.4% (27/57 chromosomally abnormal). The present study demonstrates that the postzygotic or mitotic errors leading to chromosomal mosaicism in spontaneous abortions are more frequent than previously suspected. Chromosomal mosaicism may contribute significantly to both pregnancy complications and spontaneous fetal loss.